Synthesis of optically active vitamin E

ABSTRACT

Synthesis of optically active vitamin E from 2-methyl-5-oxotetrahydro-2-furoic acid including intermediates in this synthesis.

BACKGROUND OF THE INVENTION

In the past, optically active alpha-tocopherol and derivatives thereofwhich are the 2R, 4'R, 8'R isomers of compounds of the formula: ##STR1##have been prepared through isolation from natural sources such asvegetable oil. This procedure suffers from many drawbacks due to thefact that the tocopherol content of these oils is very small. Therefore,a great amount of oil must be processed in order to isolate a smallamount of natural tocopherol. Additionally, the process whereby varioustocopherols are isolated from vegetable oil is extremely cumbersome.

SUMMARY OF INVENTION

In accordance with this invention, a process is provided forspecifically synthesizing the 2(S)-isomer of the formula: ##STR2##wherein R taken together with its attached oxygen atom forms an esterprotecting group removable by hydrolysis or an ether protecting groupremovable by hydrogenolysis or acid catalyzed cleavage.

The compound of formula II can be converted to a compound of formula Ivia a Wittig reaction with a halide salt of the formula ##STR3## whereinR₁, R₂ and R₃ are aryl, where Y is halide ion.

The compound of the formula III can be a racemate or various 3 and 7 Rand S isomers. Where the halide salt of formula III has a 3R,7Rconfiguration, i.e.: ##STR4## wherein R₁, R₂ and R₃ are as above

then natural alpha-tocopherol is produced when the 2S isomer of thecompound of formula II is utilized in the Wittig reaction.

The compound of formula II is produced in accordance with this reactionfrom a compound of the formula ##STR5##

While only the formation of the 2(S) isomer of formula II isillustrated, the compound of formula II can be produced in any desiredisomeric form depending upon the isomeric form of the compound offormula IV utilized as a starting material. If the 2R isomer of formulaIV is utilized, then the 2R isomer of formula II will be produced. If aracemate of formula IV is utilized, than a racemate of formula II isformed. The reactions utilized in accordance with this inventionmaintain the same stereoconfiguration as in the compound of formula IVthroughout its conversion to the compound of formula II.

DETAILED DESCRIPTION OF THE INVENTION

The numbering of the claims in formulas I, II, III and III-a, above, isshown for the purpose of convenience.

As used throughout this application, the term "lower alkyl" comprehendsboth straight and branched chain saturated hydrocarbon groups containingfrom 1 to 7 carbon atoms such as methyl, ethyl, propyl, isopropyl, etc.As used throughout this application, the term "halogen" includes allfour halogens, such as bromine, chlorine, fluorine and iodine. The term"alkali metal" includes sodium, potassium, lithium, etc.

In the pictorial representation of the compounds given throughout thisapplication, a () tapered line indicates a substituent which is pointedout of the plane of the paper towards the reader and the (---) brokenline indicates a substituent which is pointed into the plane of thepaper away from the reader.

The term "lower alkoxy" as used throughout the specification denoteslower alkoxy groups containing from 1 to 7 carbon atoms such as methoxy,ethoxy, propoxy, isopropoxy, etc. The term "lower alkanoyl" as usedthroughout this specification denotes lower alkanoyl groups containingfrom 2 to 6 carbon atoms such as acetyl or propionyl. As used herein theterm "aryl" designates mononuclear aromatic hydrocarbon groups such asphenyl, tolyl, etc. which can be unsubstituted or substituted in one ormore positions with a lower alkylenedioxy, a halogen, a nitro, a loweralkyl or a lower alkoxy substituent, and polynuclear aryl groups such asnaphthyl, anthryl, phenanthryl, azulyl, etc., which can be unsubstitutedor substituted with one or more of the aforementioned groups. Thepreferred aryl groups are the substituted and unsubstituted mononucleararyl groups, particularly phenyl. The term "aryl lower alkyl"comprehends groups wherein aryl and lower alkyl are as defined above,particularly benzyl. The term "aroic acid" comprehends acids wherein thearyl group is defined as above. The preferred aroic acid is benzoicacid.

As still further used herein, the term "ester protecting group removableby hydrolysis" comprehends any conventional organic acid protectinggroup which can be removed by hydrolysis. Any conventional ester thatcan be hydrolyzed to yield the acid can be utilized as the protectinggroup. Exemplary esters useful for this purpose are the lower alkylesters, particularly methyl, and the aryl esters particularly phenyl,and the aryl lower alkyl esters, particularly benzyl ester. The alcoholsutilized to form the hydrolyzable ester protecting group are loweralkanols, aryl lower alkanols and reactive derivatives thereof.

The term "ether protecting group removable by hydrogenolysis or acidcatalyzed cleavage" designates any ether which, upon acid catalyzedcleavage or hydrogenolysis yields the hydroxy group. A suitable etherprotecting group is, for example, the tetrahydropyranyl ether or4-methyl-5,6-dihydro-2H-pyranyl ether. Others are arylmethyl ethers suchas benzyl, benzhydryl or trityl ethers or alpha-lower alkoxy lower alkylether, for example, methoxymethyl or allylic ethers, or trialkyl silylethers such as trimethyl silyl ether or dimethyl-tert.-butyl silylethers. Other ethers which are preferred are tertiary butyl ethers.

The preferred ethers which are removed by acid catalyzed cleavage aret-butyl and tetrahydropyranyl. Acid catalyzed cleavage is carried out bytreatment with a strong organic or inorganic acid. Among the preferredinorganic acids are the mineral acids such as sulfuric acid, hydrohalicacid, etc. Among the preferred organic acids are lower alkanoic acidssuch as acetic acid, trifluoroacetic acid, etc. and arylsulfonic acidssuch as para-toluene sulfonic acid, etc. The acid catalyzed cleavage canbe carried out in an aqueous medium or in an organic solvent medium.Where an organic acid is utilized, the organic acid can be the solventmedium. In the case of t-butyl, an organic acid is generally utilizedwith the acid forming the solvent medium. In the case oftetrahydropyranyl ethers, the cleavage is generally carried out in anaqueous medium. In carrying out this reaction, temperature and pressureare not critical and this reaction can be carried out at roomtemperature and atmospheric pressure.

The preferred ethers which are removable by hydrogenolysis are the arylmethyl ethers such as benzyl or substituted benzyl ethers. Thehydrogenolysis can be carried out by hydrogenation in the presence of asuitable hydrogenation catalyst. Any conventional method ofhydrogenation can be utilized in carrying out this procedure. Anyconventional hydrogenation catalyst such as palladium or platinum can beutilized.

In accordance with this invention, the compound of formula VI isconverted to the compound of formula II via the following intermediates:##STR6## wherein R is as above; R₅, R₇, R₈, R₁₀ are lower alkyl.

The compound of formula IV is converted to the compound of formula V byselective reduction using a borane complex such as a borane-methylsulfide complex in the manner described in Lane et al., J. Org. Chem 39,3052 (1974). The compound of formula V is converted to the compound offormula VI by treating the compound of formula V with a compound of theformula ##STR7## wherein R₅, R₇ and R₈ are as above.

The conversion of the compound of formula V to the compound VI utilizingthe compound of formula XVI is carried out in the presence of a strongacid. Any conventional strong acid can be utilized in carrying out theprocess of this invention. Among the conventional acids are included theorganic acids such as paratoluenesulfonic acid and the inorganic acidssuch as sulfuric acid and the hydrohalic acids such as hydrochloricacid. In carrying out this reaction, an inert solvent can be utilized.Among the preferred solvents are the organic solvents such astetrahydrofuran, dioxane, etc. In carrying out this reaction,temperature and pressure are not critical and this reaction can becarried out at room temperature and atmospheric pressure. On the otherhand, elevated temperatures can be utilized. Generally, temperatures offrom 20° C. to 100° C. are utilized.

The compound of formula VI is converted to the compound of formula VIIby saponification. Any conventional method of saponification can beutilized to affect this conversion. Among the preferred methods is bytreating the compound of formula VI with a strong aqueous base andthereafter neutralizing the reaction medium. Any conventional alkalimetal base such as sodium hydroxide or potassium hydroxide can beutilized. After treatment with the strong base, the resulting reactionmixture is neutralized by treatment with a aqueous inorganic acid suchas sulfuric or hydrochloric acid. In carrying out this saponificationreaction, temperature and pressure are not critical and thesaponification reaction can be carried out at room temperature andatmospheric pressure. On the other hand, elevated temperatures andpressures can be utilized.

The conversion of the compound of formula VII to a compound of formulaVIII is carried out by first treating the compound of formula VII withN,N'-carbonyldiimidazole followed by treatment with2,5-dihydroxy-2,5-dimethyl-1,4-dithiane. This reaction can be carriedout in an inert organic solvent medium. Any conventional inert organicsolvent medium can be utilized to carry out this reaction. Among thepreferred solvents are the ether solvents such as tetrahydrofruan,dioxane, diethyl ether, etc. The preferred solvent for use in thisreaction is tetrahydrofuran. In carrying out this reaction, temperatureand pressure are not critical and this reaction can be carried out atroom temperature and atmospheric pressure. On the other hand, elevatedor reduced temperatures can be utilized. Generally, this reaction iscarried out at a temperature of from 0° C. to 100° C. with a temperatureof from 20° C. to 40° C. being preferred. In carrying out this reaction,the carbonyldiimidazole is first added. The2,5-dihydroxy-2,5-dimethyl-1,4-dithiane can be added shortly after or assoon as the addition of the carbonyldiimidazole is completed. In thisreaction, an intermediate is formed after the addition of thecarbonyldiimidazole. This intermediate has the formula: ##STR8## whereinR₇ and R₈ are as above.

The compound of formula VII-A is converted immediately upon reactionwith 2,5-dihydroxy-2,5-dimethyl-1,4-dithiane to the compound of formulaVIII. This reaction is carried out under the same conditions utilized toform the compound of formula VII-A. For instance, this reaction iscarried out in an inert organic solvent medium. Any conventional inertorganic solvent can be used as the reaction medium. Among the preferredsolvents are the ether solvents such as tetrahydrofuran. As in thereaction with the dithiane, temperature and pressure are not criticaland this reaction can be carried out at room temperature and atmosphericpressure. If desired, higher or lower temperatures can be utilized asdescribed hereinbefore.

The compound of formula VIII is converted to the compound of formula IXby treatment with a bis [tertiary amino] alkyl or arylphosphine. Anyconventional bis [tertiary amino], alkyl or aryl phosphine can beutilized. Among the preferred phosphines for use in this reaction is bis[3-dimethyl-amino-1-propyl] phenyl phosphine. The amino group in thephosphine is a tertiary amino group which is tri-substituted with loweralkyl moieties. The phosphorous substituent in the phosphine is alsomonosubstituted with either a lower alkyl or aryl substituent.Generally, this reaction is carried out in the presence of a lithiumsalt. Any conventional lithium salt such as a lithium halide can beutilized. Among the preferred lithium salts are lithium bromide, lithiumchloride, etc. In carrying out this reaction, an inert organic solventmedium is utilized. Any conventional inert organic solvent such asacetonitrile, dimethyl formamide, tetrahydrofuran, dimethyl sulfoxide,etc. In carrying out this reaction, temperatures of from 50° C. to 120°C. are generally utilized, with temperatures of from about 80° to 100°C. being preferred.

The compound of formula IX is converted to the compound of formula X byreaction with a compound of the formula ##STR9## wherein R₁₀ is loweralkyl.

This reaction is carried out in the presence of a strong base. Anyconventional strong base can be utilized. Among the preferred strongbases are the alkali metal lower alkoxides such as sodium methoxide,potassium ethoxide, etc. Generally, this reaction is carried out in aninert organic solvent. Among the preferred solvents for carrying outthis reaction are the lower alkanols such as methanol, ethanol,isopropanol, etc. In carrying out this reaction, temperature andpressure are not critical and this reaction can be carried out at roomtemperature and atmospheric pressure. On the other hand, higher or lowertemperatures can be utilized. Generally, any temperature of from 10° C.to 125° C. can be utilized, with temperatures of from about 15° C. to35° C. being preferred.

The compound of formula X is converted to the compound of formula XI bytreating the compound of formula X with an aluminum hydride reducingagent at a temperature of from 120° C. to 180° C. In carrying out thisreaction, any conventional aluminum hydride reducing agent which doesnot decompose at temperatures above 120° C., preferably from 120° C. to180° C., can be utilized to carry out this reaction. Among the preferredaluminum hydride reducing agents are sodium dihydro-bis[2-methoxyethoxy] aluminate and di(lower alkyl) aluminum hydrides suchas diisobutyl aluminum hydride. In carrying out this reaction, any inertorganic solvent can be utilized. Among the preferred inert organicsolvents are the inert organic solvents boiling above 120° C. atatmospheric pressure such as diglyme, xylene, etc. If desired, inertorganic solvents which are lower boiling can be utilized. However, ifthese low boiling inert organic solvents are utilized, the reaction iscarried out under pressure to prevent the solvent from boiling.

In accordance with another embodiment of this invention, the compound offormula X can be converted to the compound of formula XI via thefollowing intermediates: ##STR10## wherein R₇ and R₈ are as above and R₃is a lower alkanoyl.

The compound of formula X is converted to the compound of formula XVIIIby treating the compound of formula X with an aluminum hydride reducingagent at a temperature of from 0° to 100° C., preferably from 10° to 45°C. In carrying out this reaction, any conventional aluminum hydridereducing agent can be utilized. Among the preferred aluminum hydridereducing agents are included sodium aluminum hydride, diisobutylaluminum hydride, sodium bis[2-methoxyethoxy] aluminum hydride. Incarrying out this reaction, any conventional inert organic solvent canbe utilized. Among the preferred solvents for use in this inventioninclude tetrahydrofuran, dioxane, diethyl ether, benzene, toluene,xylene, etc.

The compound of formula XVIII is converted to the compound of formulaXIX by treating the compound of formula XVIII with a lower alkanoic acidor a reactive derivative thereof. Among the reactive derivatives areincluded anhydrides of lower alkanoic acids, halides of lower alkanoicacids, etc. Any conventional method for reacting an alcohol with a loweralkanoic acid or a reactive derivative thereof to form an ester can beutilized to carry out this procedure. Among the preferred lower alkanoicacids are the alkanoic acids containing from 2 to 7 carbon atoms withacetic acid or acetic anhydride being the preferred reagent for reactingwith the compound of formula XVIII.

The compound of formula XIX is converted to the compound of formula XIby treatment with an alkali metal boroydride reducing agent. Any of theconventional alkali metal borohydride reducing agents such as sodiumborohydride can be utilized for this purpose. In carrying out thisreaction, an inert organic solvent can be utilized. Among the preferredinert organic solvents are included dimethyl sulfoxide, dimethylformamide, etc. In carrying out this reaction, temperatures of from 80°C. to 125° C. are utilized.

The compound of formula XI is converted to the compound of compound XIIby oxidation with a nitroso sulfonate salt of the formula:

    O--N(SO.sub.3).sub.2 Xm                                    XXI

wherein X is an ammonium, alkali metal or alkaline earth metal ion, m isan integer of from 1 to 2 with the proviso that when X is an ammoniumion or a monovalent metal, m is 2 and when X is a divalent metal, m is1.

Among the preferred nitroso sulfonate salts are included Fremy's salt.In carrying out this reaction, any of the conditions conventional inoxidizing with Fremy's salt as well as other nitroso sulfonate salts canbe utilized. Generally, this reaction is carried out in an aqueousmedium. In carrying out this oxidation, temperature and pressure are notcritical and this reaction can be carried out at room temperature andatmospheric pressure. On the other hand, temperatures of from 0° C. to30° C. can be utilized.

The compound of formula XII can be converted to the compound of formulaXIII by treating the compound of formula XII with a strong acid in thepresence of water. In carrying out this reaction, any conventionalstrong acid can be utilized. Among the preferred strong acids areincluded the inorganic acids such as sulfuric acid and hydrohalic acids,which include hydrobromic, hydrochloric, perchloric, etc. On the otherhand, this reaction can be carried out utilizing strong organic acidssuch as the sulfonic acids. Among the strong organic acids are includedmethane sulfonic acid and para-toluene sulfonic acid. Generally, thisreaction is carried out in an aqueous medium. On the other hand, ifdesired, an inert organic solvent can be utilized in combination withwater as the reaction medium. The preferred inert organic solvents arethe polar solvents. Any conventional polar solvent can be utilized incarrying out this reaction. Among the conventional inert organic polarsolvents which can be utilized in the reaction medium are includedtetrahydrofuran, acetonitrile, ethanol, etc. In carrying out thisreaction, temperature and pressure are not critical and this reactioncan be carried out at room temperature and atmospheric pressure. On theother hand, elevated or reduced pressures and temperatures can beutilized.

In accordance with another embodiment of this invention, the compound offormula XIII can be prepared from a compound of the formula XI via thefollowing intermediates: ##STR11##

The compound of formula XI is converted to the compound of formula XXIIby acid hydrolysis. Any conventional method of acid hydrolysis can beutilized to convert the compound of formula XI to the compound offormula XXII. The compound of formula XXII is converted to the compoundof formula XXIII via oxidation with a nitroso disulfonate of the formulaXXI. This oxidation is carried on in the same manner as disclosed withregard to the oxidation of a compound of the formula XI to a compound ofthe formula XII. The compound of formula XXIII is converted to acompound of formula XIII by treatment with a strong inorganic or organicacid in the same manner as described in connection with the conversionof a compound of the formula XII to a compound of the formula XIII.However, whereas the acid treatment of the compound of formula XII iscarried out in the presence of water, the acid treatment of a compoundof the formula XXIII to a compound of the formula XIII can be carriedout in an anhydrous medium as well as in the presence of water. In theanhydrous medium, any inert organic solvent can be utilized. Among thepreferred inert organic solvents are the solvents mentioned inconnection with the conversion of the compound of formula XII to acompound of formula XIII.

The compound of formula XIII can be converted to a compound of formulaXIV by treating the compound of formula XIII with a reducing agent or bycatalytic hydrogenation. Among the preferred reducing agents are thehydride reducing agents such as disclosed hereinbefore. Any conventionalhydride reducing agent such as the aluminum hydride reducing agents andthe borohydride reducing agents can be utilized. Among the preferredhydride reducing agents are lithium aluminum hydride, sodiumbis[2-methoxyethoxy]aluminum hydride as well as the borohydride reducingagents such as sodium borohydride can be utilized. In carrying out thisreaction, any conventional inert organic solvent such as the solventsmentioned hereinbefore can be utilized as the reaction medium. Wherecatalytic hydrogenation is utilized, any conventional method ofcatalytic hydrogenation can be employed. Among the conventionalhydrogenation catalysts, noble metals such as palladium and platinumincluding compounds thereof are generally preferred. In carrying outthis conversion, temperature and pressure are not critical and roomtemperature and atmospheric pressure can be used. On the other hand,elevated or reduced temperatures and pressures can be utilized.

The compound of formula XIV is converted to the compound of formula XVby selective etherification to provide an ether protecting group, i.e. aphenolic ether protecting group removable by hydrogenolysis.

The compound of formula XV is converted to the compound of formula II byoxidation. Any conventional method of converting an alcohol to analdehyde can be utilized to affect this reaction. Among the preferredoxidizing agents for use in this reaction are included silver carbonate,a chromium trioxide pyrridine complex [Collins reagent], chromiumtrixoide dispersed in a carrier such as graphite [Lalancette reagent]and chromium trioxide in pyridine [Sarett reagent]. In carrying out thisoxidation, any of the conditions conventional in oxidizing with thesereagents can be utilized.

In accordance with another embodiment of the invention, the compound offormula XXIII can be converted to the compound of formula XIV via thefollowing intermediate ##STR12##

The compound of formula XXIII is converted to the compound of formulaXXV by hydrogenation. Any conventional method of hydrogenation can beutilized to carry out this conversion. The hydrogenation can be carriedout by hydrogenation utilizing conventional hydrogenation catalysts suchas palladium or platinum. The compound of formula XXV is converted tothe compound of formula XIV by treatment with a strong acid such asdescribed in connection with the conversion of a compound of the formulaXXII to a compound of the formula XIII.

In accordance with another embodiment of this invention, the compound ofthe formula XII can be converted to the compound of formula XIV via thefollowing intermediate: ##STR13##

The compound of formula XII is converted to the compound of formula XXVIby hydrogenation in the same manner as described in connection with theconversion of the compound of the formula XXIII to a compound of theformula XXV. The compound of the formula XXVI is converted to a compoundof the formula XIV by treating the compound of the formula XIV with astrong acid in the presence of water. Any of the acids set forth inconnection with the conversion of a compound of the formula XII to acompound of the formula XIII can be utilized in affecting thisconversion. This acid treatment is carried out at temperatures of from60° C. to 100° C. In the aqueous medium, there may be present, ifdesired, any conventional inert organic solvent. Any of the solventsmentioned hereinbefore in connection with the conversion of a compoundof formula XII to a compound of formula XIII can be utilized in thisconversion.

The following Examples are illustrative but not limitative of theinvention. All temperatures are in degrees centigrade. The ether isdiethylether in these Examples. The "usual work-up" involves threeextractions with the specified solvent. Organic solutions were thenwashed with saturated brine, dried over anhydrous MgSO₄, filtered andconcentrated on a rotary evaporator, under water aspirator pressure.Residues were dried to constant weight under high vacuum at 40°-50° orwater aspirator pressure in the case of volatile materials.

EXAMPLE 1 (S)-(+)-5-(hydroxymethyl)-5-methyldihydro-2(3H)-furanone

To a solution of 14.8 g. (102.7 mmol) of(S)-(-)-2-methyl-5-oxotetrahydro-2-furoic acid mp 84°-87° C.; [α]²⁵ D-16.56° in 70 ml. of dry tetrahydrofuran (THF) was added 10.1 ml. (8.1g.; 106.7 mmol) of borane-methyl sulphide complex, dropwise, withstirring over a 0.5 hr. period. Occasional ice-bath cooling was employedto maintain the internal temperature below 30°. After stirring at roomtemperature for 1.5 hr., the reaction mixture was cautiously decomposedby the dropwise addition of 6.2 ml. of H₂ O. The mixture was thenconcentrated under water aspirator pressure and the residue was taken upin ethyl acetate and filtered. The solids were washed thoroughly withethyl acetate and filtered. The solids were washed thoroughly with ethylacetate and the filtrate and washes were combined and concentrated invacuo giving (S)-(+)-5-(hydroxymethyl)-5-methyldihydro-2(3H)-furanone asa colorless oil (13.6 g.) which was used without further purification.

A sample of (S)-(+)-(hydroxymethyl)-5-methyldihydro-2(3H)-furanoneprepared in this way was chromatographed on 40 parts of silica gel.Elution with 1:1 parts by volume benzene-ethyl acetate and ethyl acetateyielded the pure lactone which was recrystallized from ether-ligroinegiving (S)-(+)-5-(hydroxymethyl)-5-methyldihydro-2(3H)-furanone as acolorless solid, mp 44.5°-46.5°; [α]²⁵ D +17.76° (c 1, CHCl₃).

EXAMPLE 2 (S)-(+)-2,2,4-trimethyl-1,3-dioxolane-4-propanoic acid

A solution of (S)-(+)-5-(hydroxymethyl)-5-methyldihydro-2(3H)-furanone(13.6 g.; 104.6 mmol) and 283 mg. (1.64 mmol) of p-toluenesulfonic acidmonohydrate in 161 ml. of 2,2-dimethoxy-propane was stirred at roomtemperature for 3.75 days. Pyridine (0.26 ml.) was then added and themixture concentrated under water apsirator pressure. The residual ester(S)-(+)-methyl 2,2,4-trimethyl-1,3-dioxolane-4-propanoate was dissolvedin 180 ml. of MeOH containing 29.27 g. (444 mmol) of 85% by weightaqueous KOH. The resulting solution was stirred at room temperature for4 hrs. then concentrated in vacuo. The syrupy residue was diluted withice water and the solution was extracted with ether (the ether extractwas discarded). The aqueous, alkaline solution was layered with etherand carefully acidified to pH 2.6 (pH meter) with 3 N HCl. Work up withether in the usual manner gave 16.1 g. (83.3% overall based on thefuroic acid in Example 1 of (S)-(+)-2,2,4-trimethyl-1,3-dioxolane-4-propanoic acid as an oil. This material wasused without further purification.

Crude (S)-(+)-2,2,4-trimethyl-1,3-dioxolane-4-propanoic acid wasevaporatively distilled giving pure(S)-(+)-2,2,4-trimethyl-1,3-dioxolane-4-propanoic acid as a colorlessoil, bp 80°-90° (bath temperature) (0.15 mmHg); [α]²⁵ D +1.58° (c 2.02,CHCl₃).

EXAMPLE 3 (S)-(+)-methyl 2,2,4-trimethyl-1,3-dioxolane-4-propanoate

A solution of 6.3 g. (48.5 mmol) of(S)-(+)-5-(hydroxymethyl)-5-methyldihydro-2(3H)-furanone and 133 mg. ofp-toluenesulfonic acid monohydrate in 75 ml. of 2,2-dimethoxypropane wasstirred and refluxed for 3.5 hr. then cooled in an ice bath, dilutedwith ether and washed with saturated aqueous NaHCO₃ solution. Theorganic solution was processed in the usual manner giving 8.2 g. of ayellow oil. This material was chromatographed on 400 g. of silica gel.Elution with 9:1 parts by volume and 4:1 parts by volume benzene-ethylacetate gave the ester (S)-(+)-methyl2,2,4-trimethyl-1,3-dioxolane-4-propanoate which was evaporativelydistilled yielding 4.6 g. (47%) of a colorless liquid, bp 90°-100° (bathtemperature) (12 mmHg); [α]²⁵ D +1.74° (c 2, C₆ H₆). An analyticalspecimen of (S)-(+)-methyl 2,2,4-trimethyl-1,3-dioxolane-4-propanoatewas obtained by rechromatography and redistillation of a sample; [α ]²⁵D +2.97° (c 2, C₆ H₆).

EXAMPLE 4 (S)-(+)-4-(3,5-dioxo-1-hexyl)-2,2,4-trimethyl-1,3-dioxolane

To a stirred solution of 10 g. (53.2 mmol) of(S)-(+)-2,2,4-trimethyl-1,3-dioxolane-4-propanoic acid in 100 ml. ofanhydrous THF was cautiously added 9.04 g. (55.8 mmol) ofN,N'-carbonyldiimidazole (gas evolution). The resulting solution wasstirred for 1 hour at room temperature then treated with 4.78 g. (26.6mmol) of 2,5-dihydroxy-2,5-dimethyl-1,4-dithiane. Stirring was continuedfor 4 hrs. at room temperature then the reaction mixture was dilutedwith water and worked up with ether in the usual manner. The orange,oily residue (14.3 g.) was chromatographed on silica gel (400 g.).Elution with 9:1 parts by volume and 4:1 parts by volume benzene-ethylacetate yielded 11.1 g. (80.2%) of thiol ester(S)-3-(2,2,4-trimethyl-1,3-dioxolan-4-yl)propanoic acid2-oxopropyl-S-ester as a yellow oil.

To a solution of 10.6 g. (40 mmol) of this thiol ester in 32 ml. of dryCH₃ CN was added 3.85 g. (44.4 mmol) of anhydrous LiBr. After solutionhad occurred, 33 g. (123 mmol) ofbis(3-dimethyl-amino-1-propyl)phenylphosphine was added. Separation of asolid soon began as the mixture was stirred and heated at 85°-90° C.After heating for 4.5 hr., the reaction mixture was cooled and pouredinto ice-water. The aqueous phase was layered with ether and acidifiedto pH 3.3 (pH meter) by the dropwise addition of 3N aqueous HCl. Work-upwith ether in the usual manner gave 8.7 g. of crude product as a yellowoil. This material was chromatogaphed on 350 g. of silica gel. Elutionwith 4:1 and 2:1 parts by volume hexane-ether gave the(S)-(+)-4-(3,5-dioxo-1-hexyl)-2,2,4-trimethyl-1,3-dioxolane which wasevaporatively distilled. There was obtained 6.57 g. (72%) of pure(S)-(+)- 4-(3,5-dioxo-1-hexyl)-2,2,4-trimethyl-1,3-dioxolane as apale-yellow oil, bp 95°-105° (bath temperature) (0.005 mmHg); [α]²⁵ D+8.54° (c, 2, CHCl₃).

Basification of the acidic aqueous solution followed by ether extractionallowed recovery of the excess phosphine reagent.

EXAMPLE 5 (S)-(+)-dimethyl2-hydroxy-6-methyl-4-(2,2,4-trimethyl-1,3-dioxolane-4-ethyl)-1,3-benzenedicarboxylate

A solution of 6.0 g (26.3 mmol) of(S)-(+)-4-(3,5-dioxo-1-hexyl)-2,2,4-trimethyl-1,3-dioxolane from thepreceding example and 5.83 g. (33.4 mmol) of dimethyl1,3-acetonedicarboxylate in 33.6 ml. of 0.85 M methanolic NaOMe wasstirred at room temperature for 21 hrs. The resulting yellow solutionwas poured into ice-water, layered with ether and the pH was adjusted to3 by the addition of 3 N aqueous HCl. Work-up with ether in the usualmanner gave 10.9 g. of a yellow oil. This material was chromatographedon 350 g. of silica gel. Elution with 9:1 and 4:1 parts by volumebenzene-ethyl acetate gave 8.82 g. (91.7%) of (S)-(+)-dimethyl2-hydroxy-6-methyl-4-(2,2,4-trimethyl-1,3-dioxolane-4-ethyl)-1,3-benzenedicarboxylateas a yellow oil; [α]²⁵ D +5.44° (c, 2, CHCl₃); Gc analysis indicated apurity of 92.4%. An analytical specimen was obtained by carefulrechromatography and evaporative distillation giving pure(S)-(+)-dimethyl2-hydroxy-6-methyl-4-(2,2,4-trimethyl-1,3-dioxolane-4-ethyl)-1,3-benzenedicarboxylateas a viscous, pale yellow oil, bp 125°-130° (bath temperature) (0.003mmHg); [α]²⁵ D +6.07° (c, 2, CHCl₃).

EXAMPLE 6(S)-(+)-2-hydroxy-6-methyl-4-(2,2,4-trimethyl-1,3-dioxolane-4-ethyl)benzene-1,3-dimethanoltriacetate

To a solution of 6.35 g. (17.3 mmol) of (S)-(+)-dimethyl2-hydroxy-6-methyl-4-(2,2,4-trimethyl-1,3-dioxolane-4-ethyl)-1,3-benzenedicarboxylatein 138 ml. of anhydrous ether was added, dropwise, with stirring, 29 ml.of 70% sodium bis(2-methoxyethoxy)aluminum hydride in benzene. Thereaction mixture was stirred at room temperature for 4 hrs. then atreflux for 16.5 hrs. After cooling, the mixture was cautiously pouredonto ice-water. The aqueous phase was adjusted to pH 3.5 by the dropwiseaddition of 3N aqueous HCl. Work-up with ether in the usual manner gave4.44 g. (82.8%) of(S)-(+)-2-hydroxy-6-methyl-4-(2,2,4-trimethyl-1,3-dioxolane-4-ethyl)benzene-1,3-dimethanolas a yellow oil. This material was dissolved in 14.2 ml. of dry pyridinecontaining 6.5 ml. of acetic anhydride and the solution was stirred for4.5 hrs. at room temperature then treated with 200 ml. of H₂ O. Excesssolid NaHCO₃ was added, followed by ether and the mixture was stirredfor 15 min. The ether layer was separated and the aqueous layer wasextracted three more times with ether. The combined ether extracts werestirred with 100 ml. of H₂ O while the pH of the aqueous phase wasadjusted to 4 by the addition of 3 N aqueous HCl. Work-up in the usualmanner (the ether extracts were additionally washed with NaHCO₃solution) gave 6.25 g. of(S)-(+)-2-hydroxy-6-methyl-4-(2,2,4-trimethyl-1,3-dioxolane-4-ethyl)benzene-1,3-dimethanoltriacetate as an oil which was used without further purification. An 0.5g. sample of this material was chromatographed on 50 parts of silicagel. Elution with ether gave 0.33 g. of pure(S)-(+)-2-hydroxy-6-methyl-4-(2,2,4-trimethyl-1,3-dioxolane-4-ethyl)benezene-1,3-dimethanoltriacetate as a viscous, colorless oil; [α]²⁵ D +5.49° (c 2, CHCl₃).

EXAMPLE 7(S)-(+)-2,3,6-trimethyl-5-(2,2,4-trimethyl-1,3-dioxolane-4-ethyl)phenol

To a solution of 5.75 g. of the crude(S)-(+)-2-hydroxy-6-methyl-4-(2,2,4-trimethyl-1,3-dioxolane-4-ethyl)benzene-1,3-dimethanoltriacetate in 140 ml. of anhydrous dimethyl sulfoxide was added 4.96 g.(130 mmol) of NaBH₄. The resulting mixture was stirred and heated at90°-100° for 4 hrs. then cooled and treated with 29 ml. of 1 N NaOH.After stirring for 1 hr. at room temperature, the mixture was dilutedwith ice-water (500 ml.) and acidified to pH 3.8 with 3 N HCl. Work-upwith ether in the usual manner (the extracts were additionally washedwith H₂ O and saturated NaHCO₃ solution) gave 3.14 g. of a pale yellowoil. This material was chromatographed on 150 g. of silica gel. Elutionwith 19:1 and 9:1 parts by volume benzene-ethyl acetate afforded 2.5 g.of pure(S)-(+)-2,3,6-trimethyl-5-(2,2,4-trimethyl-1,3-dioxolane-4-ethyl)-phenolas a colorless oil which crystallized, mp 53°-60.5°. A portion of thismaterial was recrystallized from hexane giving a colorless solid, mp60°-62°; [α]²⁵ D +5.00° (c 2.0, CHCl₃).

EXAMPLE 8

A solution of 1.02 g. (2.79 mmol) of (S)-(+)-dimethyl2-hydroxy-6-methyl-4-(2,2,4-trimethyl-1,3-dioxolane-4-ethyl)-1,3-benzenedicarboxylatein 5 ml. of xylene was added, dropwise, over a 5 min. period, to astirred solution of 6 ml. (21.7 mmol) of 70% NaAlH₂ (OCH₂ CH₂ OMe)₂ (inbenzene) in 5 ml. of xylene. The resulting solution was stirred andrefluxed for 3.75 hrs. then cooled to 10° at which point a solution of1.16 ml. of conc. H₂ SO₄ in 5 ml. of H₂ O was cautiously added,dropwise. The resulting slurry was diluted with 23 ml. of MeOH andstirred and refluxed for 10 min. After cooling, the slurry ws filteredand the granular solid was washed with MeOH and then ether. The filtrateand washes were combined and concentrated in vacuo. The residue wastaken up in ether and the solution was washed with brine and processedin the usual manner to give 769 mg. of a yellow oil. This material waschromatographed on 30 g. of silica gel. Elution with 4:1, 2:1 and 1:1(parts by volume) hexane-ether afforded 640 mg. (82.5%) of(S)-(+)-2,3,6-trimethyl-5-(2,2,4-trimethyl-1,3-dioxolane-4ethyl)phenolas a colorless oil which crystallized.

EXAMPLE 9(S)-(+)-2,3,6-trimethyl-5-(2,2,4-trimethyl-1,3-dioxolane-4-ethyl)-p-benzoquinone

A solution of 2.02 g. (7.66 mmol) of(S)-(+)-2,3,6-trimethyl-5-(2,2,4-trimethyl-1,3-dioxolane-4-ethyl)phenolin 81 ml. of MeOH was added to a solution prepared from 65 g. (excess)of a slurry of disodium nitrosodisulfonate (Fremy's salt) in aqueous Na₂CO₃, 16 ml. of 1 N aqueous NaOAc and 484 ml. of H₂ O. The brown mixturewas stirred at room temperature for 1.5 hrs. then worked-up with etherin the usual manner. There was obtained 2.07 g. (97.6%) of essentiallypure(S)-(+)-2,3,6-trimethyl-5-(2,2,4-trimethyl-1,3-dioxolane-4-ethyl)-p-benzoquinoneas a viscous orange oil which was used without further purification. Asample was chromatographed on silica gel (50 parts). Elution with 4:1parts by volume hexane-ether afforded an analytical specimen of(S)-(+)-2,3,6-trimethyl-5-(2,2,4-trimethyl-1,3-dioxolane-4-ethyl)-p-benzoquinoneas a viscous orange oil, [α]²⁵ D +6.39° (c 2, CHCl₃).

EXAMPLE 10(S)-(+)-5-(3,4-dihydroxy-3-methyl-1-butyl)-2,3,6-trimethylphenol

A solution of 1.4 g. (5.04 mmol) of(S)-(+)-2,3,6-trimethyl-5-(2,2,4-trimethyl-1,3-dioxolane-4-ethyl)phenolin 28 ml. of MeOH and 5.5 ml. of 1 N aqueous HCl was stirred at roomtemperature for 20 hrs. then poured into satruated brine and worked-upwith ether in the usual manner. Trituration of the solid residue withether afforded 0.8 g. (66.7%) of pure(S)-(+)-5-(3,4-dihydroxy-3-methyl-1-butyl)-2,3,6-trimethylphenol as acolorless solid, mp 145°-146°; [α]²⁵ D +2.20° (c 2, EtOH).

The ether filtrate from the above trituration was concentrated and theresidue was recrystallized from ethyl acetate giving an additional 139mg. (11.7%) of(S)-(+)-5-(3,4-dihydroxy-3-methyl-1-butyl)-2,3,6-trimethylphenol.

EXAMPLE 11(S)-(+)-5-(3,4-dihydroxy-3-methyl-1-butyl)-2,3,6-trimethyl-p-benzoquinone

An 0.5 g. (2.1 mmol) sample of(S)-(+)-5-(3,4-dihydroxy-3-methyl-1-butyl)-2,3,6-trimethyl-phenol wastreated with Fremy's salt as in Example 9. There was obtained 480 mg.(90.7%) of(S)-(+)-5-(3,4-dihydroxy-3-methyl-1-butyl)-2,3,6-trimethyl-p-benzoquinoneas a yellow solid, mp 109°-112.5°. Recrystallization from CHCl₃ -hexanegave 370 mg. of yellow solid, mp 11.5°-113°; [α]²⁵ D +6.28° (c 2,CHCl₃).

EXAMPLE 12(3S,9aR)-(-)-2,3,4,5,7,9a-hexahydro-3,6,8,9-tetramethyl-3,9a-epoxy-1-benzoxepin-7-one

A solution of 1.5 g. (5.13 mmol) of(S)-(+)-2,3,6-trimethyl-5-(2,2,4-trimethyl-1,3-dioxolane-4-ethyl)-p-benzoquinonein 42 ml. of MeOH containing 8.3 ml. of 1 N aqueous HCl was stirred atroom temperature for 18 hrs. then poured into saturated brine andworked-up with ether in the usual manner (the ether extracts wereadditionally washed with saturated aqueous NaHCO₃). The yellow solidproduct obtained (1.27 g.) was chromatographed on silica gel (100 g.) toremove a small amount of(S)-(+)-5-(3,4-dihydroxy-3-methyl-1-butyl)-2,3,6-trimethyl-p-benzoquinone.Elution with 19:1 and 9:1 (parts by volume) benzene-ethyl acetateyielded 870 mg. (72.5%) of(3S,9aR)-(-)-2,3,4,5,7,9a-hexahydro-3,6,8,9-tetramethyl-3,9a-epoxy-1-benzoxepin-7-oneas a colorless solid, mp 99°-100° C.; [α]²⁵ D -56.04° (c 2, C₆ H₆).

EXAMPLE 13

An 0.2 g. (0.8 mmol) sample of(S)-(+)-5-(3,4-dihydroxy-1-butyl)-2,3,6-trimethyl-p-benzoquinone wastreated as in Example 12. The crude product (219 mg.) waschromatographed as above giving 157 mg. (84.8%) of pure(3S,9aR)-(-)-2,3,4,5,7,9a-hexahydro-3,6,8,9-tetramethyl-3,9a-epoxy-1-benzoxepin-7-oneas a colorless solid, mp 96°-100°; [α]²⁵ D -54.29° (c 2.2, C₆ H₆).

EXAMPLE 14 (S)-(+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-methanol

To a stirred solution of 787 mg. (3.36 mmol) of(3S,9aR)-(-)-2,3,4,5,7,9a-hexahydro-3,6,8,9-tetramethyl-3,9a-epoxy-1-benzoxepin-7-onein 8.5 ml. of dry THF, at 0° C., was added 0.94 ml. (6.72 mmol) of 70%by weight NaAlH₂ (OCH₂ CH₂ OMe)₂ solution in benzene, dropwise. Thereaction mixture was stirred at 0° for 1 hr., then poured onto a mixtureof ice and 1 N aqueous HCl. Work-up in the usual manner with etherafforded 717 mg. of solid product which was chromatographed on 50 g. ofsilica gel. Elution with 9:1, 4:1 and 2:1 parts by volume benzene-ethylacetate yielded 647 mg. (81.6%) of pure(S)-(+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-methanol as a colorlesssolid, mp 127°-129°; [α]²⁵ D +1.44° (c 2, EtOH).

EXAMPLE 15

A mixture of 200 mg. (0.834 mmol) of(3S,9aR)-(-)-2,3,4,5,7,9a-hexahydro-3,6,8,9-tetramethyl-3,9a-epoxy-1-benzoxepin-7-oneand 223 mg. of powdered zinc in 10 ml. of glacial acetic acid wasstirred at room temperature for 47 hrs. The mixture was then dilutedwith water, neutralized with NaHCO₃ and worked-up with ether in theusual manner. The crude, oily product (212 mg.) was chromatographed on20 g. of silica gel. Elution with 19:1 and 9:1 (parts by volume)benzene-ethyl acetate gave 140 mg. (70%) of recovered(3S,9aR)-(-)-2,3,4,5,7,9a-hexahydro-3,6,8,9-tetramethyl-3,9a-epoxy-1-benzoxepin-7-one,mp 97°-99.5°. Further elution with 4:1 and 2:1 benzene-ethyl acetateafforded 60 mg. (30%) of(S)-(+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-methanol as a colorlesssolid, mp 123°-127°.

EXAMPLE 16

A mixture of 200 mg. (0.834 mmol) of(3S,9aR)-(-)-2,3,4,5,7,9a-hexahydro-3,6,8,9-tetramethyl-3,9a-epoxy-1-benzoxepin-7-one,200 mg. of 5% by weight palladium on 95% by weight charcoal and 50 ml.of ethanol was stirred in an atmosphere of hydrogen until gas uptakeceased (30 ml. H₂ consumed). The catalyst was filtered and the filtratewas concentrated in vacuo. Chromatography of the crude product on 20 g.of silica gel gave 150 mg. (76.2%) of(S)-(+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-methanol as a colorlesssolid, mp 119°-125° C. [eluted with 4:1 and 2:1 (parts by volume)benzene-ethyl acetate].

EXAMPLE 17 (S)-(-)-6-benzyloxy-2,5,7,8-tetramethylchroman-2-methanol

A mixture of 0.55 g. (2.33 mmol) of(S)-(+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-methanol, 790 mg. (5.72mmol) of anhydrous K₂ CO₃, 0.68 ml. (748 mg; 5.93 mmol) of benzylchloride (distilled from and stored over K₂ CO₃) and 4.5 ml. of DMF wasstirred for 22 hrs. at room temperature then poured into H₂ O and workedup with ether in the usual manner. There was obtained 0.89 g. of ayellow oily product which was chromatographed on silica gel (35 g.).Elution with 19:1 and 9:1 benzene-ethyl acetate gave 724 mg. (97.1%) of(S)-(-)-6-benzyloxy-2,5,7,8-tetramethylchroman-2-methanol as a colorlesssolid, mp 66°-69.5°; [α]²⁵ D -2.35° (c 1.2, CHCl₃).

EXAMPLE 18(S)-(+)-6-benzyloxy-2,5,7,8-tetramethylchroman-2-carboxaldehyde

To a stirred mixture of 36 ml. of dry CH₂ Cl₂, 2.8 ml. of dry pyridineand 1.46 g. (14.6 mmol) of CrO₃ was added a solution of 645 mg. (1.98mmol) of (S)-(-)-6-benzyloxy2,5,7,8-tetramethylchroman-2-methanol in 5ml. of CH₂ Cl₂. The dark mixture was stirred for 40 min. at roomtemperature then the organic solution was decanted and the dark residuewas washed with ether and CH₂ Cl₂. The combined organic solutions werediluted with ether, washed with 1 N NaOH, H₂ O and 1 N HCl and work-upwas then completed in the usual manner. The yellow oily product (590mg.) was chromatographed on 50 g. of silica gel. Elution with 19:1(parts by volume) hexane-ether gave 492 mg. (76.7%) of pure(S)-(+)-6-benzyloxy-2,5,7,8-tetramethylchroman-2-carboxyaldehyde as anoil which crystallized yielding a colorless solid, mp 56°-58°; [α]²⁵ D+11.89° (c 5.2, CHCl₃).

EXAMPLE 19 (2R,4'R,8'R)-α-tocopheryl-acetate

A solution of 570 mg. (1.03 mmol) of(3R,7R)-hexahydrofarnesyltriphenylphosphonium bromide in 5.6 ml. ofanhydrous dimethoxyethane was stirred at room temperature while 0.43 ml.(1.03 mmol) of 2.4 M n-butyllithium in hexane was added. The resultingred solution was stirred for 2 hrs. at room temperature then a solutionof 153 mg. (0.472 mmol) of(S)-(+)-6-benzyloxy-2,5,7,8-tetramethylchroman-2-carboxaldehyde in 1.5ml. of anhydrous DME was added and stirring was continued for 3 hrs. at65°-70°. After cooling, the reaction mixture was poured onto cold,dilute H₂ SO₄ and work-up with ether was carried out in the usualmanner. The product (520 mg.) was a mixture of oil and solid which wastriturated with hexane. The hexane solution was decanted andconcentrated in vacuo affording 287 mg. of oily material which waschromatographed on 15g. of silica gel. Elution with 19:1 (parts byvolume) hexane-ether yielded 168 mg. (68.7%) of 1',2'-dehydrotocopherolbenzyl ether as a colorless oil. This material (165 mg; 0.318 mmol) in15 ml. of ethyl acetate was stirred with 68 mg. of 5% palladium oncarbon, in an atmosphere of H₂, until gas uptake ceased. The catalystwas filtered and the filtrate was concentrated in vacuo giving 120 mg.(88.2%) of (2R,4'R,8'R)-α-tocopherol as a colorless oil which washomogeneous on tlc analysis. The ir and nmr spectra of this materialwere identical with those of natural d-α-tocopherol.

A solution of 112 mg. (0.26 mmol) of this material in 0.75 ml. of drypyridine and 0.59 ml. of acetic anhydride was stirred at roomtemperature for 17 hrs. then concentrated under high vacuum. The residuewas taken up in hexane and the solution was washed with H₂ O and brineand processed in the usual manner. The oily product was chromatographedon 7 g. of silica gel. Elution with 9:1 parts by volume hexane-ethergave (2R,4'R,8'R)-α-tocopheryl acetate (105 mg.). Evaporativedistillation yielded 90 mg. (73.7%) of colorless oil, bp 205°(bathtemperature) (0.02 mmHg).

EXAMPLE 20

A solution of 0.405g (1.6mmoles) of(S)-(+)-5-(3,4-dihydroxy-3-methyl-1-butyl)-2,3,6-trimethyl-p-benzoquinonein 20 ml of ethyl acetate was stirred in an atmosphere of hydrogen, inthe presence of 0.04g of 5% by weight palladium on 95% by weightcharcoal until H₂ uptake ceased (ca. 1hr; 38 ml H₂ absorbed). Thecatalyst was filtered and the filtrate was concentrated giving 0.41 g of(S)-5-(3,4-dihydroxy-3-methyl-1-butyl)-2,3,6-trimethylhydroquinone as atan solid, mp 124°-131.5°.

EXAMPLE 21

A mixture of 0.32g (1.26 mmoles) of(S)-5-(3,4-dihydroxy-3-methyl-1-butyl)-2,3,6-trimethylhydroquinone, 25mg of p-toluene sulfonic acid monohydrate and 25 ml of benzene wasstirred and refluxed for 1.25 hr. The resulting solution was cooled,washed with NaHCO₃ solution and processed in the usual manner giving0.393g of a semi-solid residue which was chromatographed on 25g ofsilica gel. Elution with 9:1, 4:1 and 2:1 (parts by volume)toluene-ethyl acetate yielded 0.237g (79.7%) of(S)-(+)-6-hydroxy2,5,7,8-tetramethylchroman-2-methanol as acream-colored solid, mp 122°-124° C.; [α]_(D) +1.09° (c 2.195, EtOH).

EXAMPLE 22

A 0.531g (1.82 mmoles) sample of(S)-(+)-2,3,6-trimethyl-5-(2,2,4-trimethyl-1,3-dioxolane-4-ethyl)-p-benzoquinonewas hydrogenated as described above in example 20. A total of 50 ml ofH₂ was absorbed. There was obtained 0.54g of(S)-2,3,6-trimethyl-5-(2,2,4-trimethyl-1,3-dioxolane-4-ethyl)hydroquinoneas a tan solid.

EXAMPLE 23

A solution of 0.455g (1.54 mmoles) of(S)-2,3,6-trimethyl-5-(2,2,4-trimethyl-1,3-dioxolane-4-ethyl)hydroquinoneand 2 ml of 1 N aqueous sulfuric acid in 10 ml of methanol was stirredand refluxed for 1.5 hr. After cooling, the reaction mixture was treatedwith saturated brine and worked-up with ether in the usual manner giving0.362g of a brown glass. This material was triturated with ether givinga solid which was removed by filtration. The ether solution waschromatographed on 25g of silica gel. Elution with 4:1 and 2:1toluene-ethyl acetate afforded 0.125g (34.4%) of(S)-(+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-methanol as a colorlesssolid, mp 124.5°-127.5°; [α]_(D) ²⁵ +1.04°(c 2.115, EtOH).

We claim:
 1. A compound of the formula ##STR14## wherein R₃ is methyl or##STR15## and R₄, R₇ and R⁸ are lower alkyl.
 2. The compound of claim 1wherein said compound is (S)-(+)-dimethyl2-hydroxy-6-methyl-4-(2,2,4-trimethyl-1,3-dioxolane-4-ethyl)-1,3-benzenedicarboxylate.3. The compound of claim 1 wherein said compound is(S)-(+)-2,3,6-trimethyl-5-(2,2,4-trimethyl-1,3-dioxolane-4-ethyl)phenol.4. A compound of the formula ##STR16## wherein R₃ is hydrogen or loweralkanoyl; R₇ and R₈ are lower alkyl.
 5. The compound of claim 4 whereinsaid compound is(S)-(+)-2-hydroxy-6-methyl-4-(2,2,4-trimethyl-1,3-dioxolane-4-ethyl)benzene-1,3-dimethanol.6. The compound of claim 4 wherein said compound is(S)-(+)-2-hydroxy-6-methyl4-(2,2,4-trimethyl-1,3-dioxolane-4-ethyl)benzene-1,3-dimethanoltriacetate.